Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Amodio, Nicola; Scrima, Marianna; Palaia, Lucia; Salman, Ali Naeem; Quintiero, Alfina; Franco, Renato; Botti, Gerardo; Pirozzi, Pino; Rocco, Gaetano; Rosa, Nicla De; Viglietto, Giuseppe

doi:10.2353/ajpath.2010.091075

Cited by 127 publications

(133 citation statements)

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“…The Nedd4-IRS-2 binding may represent a novel drug target at least in prostate cancer. Accumulating evidence suggests that Nedd4 is overexpressed in various cancers and functions as a tumour-promoting factor [17][18][19][20][21] . It is important to investigate the contribution of the Nedd4-IRS-2 complex to the development of various cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Nedd4 knockout mice show fetal growth retardation and perinatal lethality 16 , indicating a crucial role for Nedd4 in embryonic growth. Nedd4 is overexpressed in several types of cancers and functions as an oncogenic protein [17][18][19][20][21] . We provide multiple lines of evidence, suggesting that Nedd4 conjugates monoubiquitin to IRS-2 and recruits IRS-2 to the plasma membrane, thereby enhancing IRS-2 tyrosine phosphorylation by IGF-IR and IGF-I mitogenic activity.…”

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confidence: 99%

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Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

et al. 2015

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

et al. 2015

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“…44 Antibodies specific for total Akt, phospho-Akt (Ser473) and for caspase3/7, ERK1/2, phospho-ERK1/2 (Thr202/Tyr204), LC3BII were obtained from Cell Signaling Technologies.…”

mentioning

confidence: 99%

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

Marvaso

Barone

Amodio

et al. 2014

Cancer Biology & Therapy

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Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment

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“…But the dominant views are still that the oncogenic activity of NEDD4 depends on the degradation of PTEN. Amodio et al 18 have demonstrated that NEDD4 is overexpressed in human NSCLC, and the overexpression of NEDD4 leads to an increase of the ubiquitylated form of PTEN, thereby reducing PTEN levels and increasing Akt activation. Ahn et al 35 also confirmed that NEDD4 can inhibit PTENinduced apoptosis in cells; in addition, PTEN can act as a feedback regulator for NEDD4 and transcriptionally regulate the expression of NEDD4.…”

Section: Discussionmentioning

confidence: 99%

“…17 Inverse relationships between the expression of NEDD4 and PTEN have also been observed in human NSCLC. 18 However, recent work failed to find the relationship between NEDD4-mediated PTEN degradation and acquired resistance to EGFR-TKIs in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

Sun

Wang

et al. 2017

Tumour Biol.

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Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer. KeywordsPhosphatase and tensin homolog deleted on chromosome 10 degradation, NEDD4, acquired tyrosine kinase inhibitor resistance, non-small-cell lung cancer Date

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Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Cited by 127 publications

References 35 publications

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

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